Developmental Disorders of the Lymphatics

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Wednesday, December 07, 2005



OL-EDA-ID Syndrome



A number sign (#) is used with this entry because the phenotype is caused by hypomorphic mutations in NEMO (IKBKG; 300248).

Doffinger et al. (2001) examined 2 unrelated male patients who presented with the novel OL-EDA-ID syndrome. Both were sons of mothers with mild incontinentia pigmenti (308300), and both died of overwhelming multiple infections at 2.5 and 1.5 years of age, respectively. Both had osteopetrosis, lymphedema, and anhidrotic ectodermal dysplasia. Immunologic variables in the second patient showed a poor inflammatory response and increases in the levels of blood inflammatory markers with fever either absent or delayed during infection. Blood monocytes and polymorphonuclear cells were normal in number and morphology. The B- and T-cell counts and responses to vaccine protein antigens were normal. Serum titers of antibodies against S. pneumoniae were low, despite proven infection. Serum titers of isohemagglutinins were low. Serum levels of immunoglobulin isotypes were normal for age, with the exception of low to normal IgG levels. Both patients carried an X420W mutation in IKBKG, or NEMO (300248.0002). Different alleles were present at the flanking polymorphic loci in the 2 patients, indicating 2 independent mutational events. Both patients died of overwhelming infectious disease caused by a variety of microorganisms, including gram-positive cocci, gram-negative bacilli, mycobacteria, and fungi. There were impaired cellular responses to TNF-alpha (191160).

Doffinger et al. (2001) compared the induction of IFN-gamma (147570) by peripheral blood mononuclear cells (PBMC) from one of the patients and a control. The patient's PBMC displayed a lower level of IFN-gamma production upon costimulation with IL12 (see 161560) and various concentrations of IL1-beta (147720) or IL18 (600953) than the control PBMC. There were impaired cellular responses to lipopolysaccharide in this patient. The patient also exhibited dissociated cellular responses to CD154 (CD40LG; 300386), suggesting that some but not all CD40 (109535)-mediated signals are NEMO-dependent in both dentritic cells and B cells.


H. Doffinger, R.; Smahi, A.; Bessia, C.; Geissmann, F.; Feinberg, J.; Durandy, A.; Bodemer, C.; Kenwrick, S.; Dupuis-Girod, S.; Blanche, S.; Wood, P.; Rabia, S. H.; and 16 others :
X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappa-B signaling. Nature Genet. 27: 277-285, 2001.PubMed ID :

Pub Med


Osteopetrosis, Lymphedema, Anhidrotic Ectodermal Dysplasia, and Immunodeficiency in a Boy and Incontinentia Pigmenti in His Mother



X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB signaling.

Doffinger R, Smahi A, Bessia C, Geissmann F, Feinberg J, Durandy A, Bodemer C, Kenwrick S, Dupuis-Girod S, Blanche S, Wood P, Rabia SH, Headon DJ, Overbeek PA, Le Deist F, Holland SM, Belani K, Kumararatne DS, Fischer A, Shapiro R, Conley ME, Reimund E, Kalhoff H, Abinun M, Munnich A, Israel A, Courtois G, Casanova JL.Laboratoire de Genetique Humaine des Maladies Infectieuses, Faculte de Medecine Necker-Enfants Malades, Paris, France.

The molecular basis of X-linked recessive anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) has remained elusive. Here we report hypomorphic mutations in the gene IKBKG in 12 males with EDA-ID from 8 kindreds, and 2 patients with a related and hitherto unrecognized syndrome of EDA-ID with osteopetrosis and lymphoedema (OL-EDA-ID). Mutations in the coding region of IKBKG are associated with EDA-ID, and stop codon mutations, with OL-EDA-ID. IKBKG encodes NEMO, the regulatory subunit of the IKK (IkappaB kinase) complex, which is essential for NF-kappaB signaling. Germline loss-of-function mutations in IKBKG are lethal in male fetuses. We show that IKBKG mutations causing OL-EDA-ID and EDA-ID impair but do not abolish NF-kappaB signaling. We also show that the ectodysplasin receptor, DL, triggers NF-kappaB through the NEMO protein, indicating that EDA results from impaired NF-kappaB signaling. Finally, we show that abnormal immunity in OL-EDA-ID patients results from impaired cell responses to lipopolysaccharide, interleukin (IL)-1beta, IL-18, TNFalpha and CD154. We thus report for the first time that impaired but not abolished NF-kappaB signaling in humans results in two related syndromes that associate specific developmental and immunological defects.

Publication Types:
Case Reports
PMID: 11242109 [PubMed - indexed for MEDLINE]


Anhidrotic ectodermal dysplasia and immunodeficiency: the role of NEMO

E D Carrol1, A R Gennery1, T J Flood1, G P Spickett2 and M Abinun1
1 Department of Paediatric Immunology, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK2 Regional Immunology Department, Newcastle upon Tyne Hospitals NHS Trust
Correspondence to:Dr M Abinun, Department of Paediatric Immunology, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne NE4 6BE, UK;
Accepted for publication 10 October 2002


Anhidrotic (hypohidrotic) ectodermal dysplasia associated with immunodeficiency (EDA-ID; OMIM 300291) is a newly recognised primary immunodeficiency caused by mutations in NEMO, the gene encoding nuclear factor B (NF-B) essential modulator, NEMO, or inhibitor of B kinase (IKK-). This protein is essential for activation of the transcription factor NF-B, which plays an important role in human development, skin homoeostasis, and immunity.
Keywords: anhidrotic ectodermal dysplasia; immunodeficiency; NEMO; NF-B
We present an update on the first reported patient with EDA-ID syndrome
1 subsequently shown to be caused by NEMO mutation,2 and our current understanding of this rare primary immunodeficiency.

Immunodeficiency is an important feature of many rare congenital and hereditary conditions involving multiple organs and systems3 (for example, IPEX—immunodeficiency, polyendocrinopathy, enteropathy, X linked; ICF—immunodeficiency, chromosomal instability, facial anomalies; Netherton syndrome, Schimke immuno-osseous dysplasia, etc). For many of these conditions underlying gene mutations have been recently identified, leading to our better understanding of functions of the immune system. From the practical point of view, recognising that immunodeficiency is part of the broader syndrome is important as the majority of care of these rare and complex patients is supervised locally by general paediatricians. Understanding of the interrelation of the problems these patients face allows previously unrecognised complications to be actively sought and treated.


We previously described a 4 year old white boy with clinical features of X linked anhidrotic ectodermal dysplasia who suffered from recurrent life threatening infections caused by Streptococcus pneumoniae. We found that he had associated specific antibody deficiency (SPAD), in particular antipolysaccharide antibody deficiency.1 He initially responded well to intravenous immunoglobulin (IVIg) replacement, but as one of the possible explanations for his SPAD was a maturational delay of the immune system, this was stopped after two years and his specific antibody production was reassessed. The original diagnosis was confirmed, as well as low IgG2 subclass level and very low specific antibody response to tetanus toxoid. He was recommenced on IVIg replacement, and at follow up at age 11 years he has remained free of major infections with no evidence of bronchiectasis on high resolution chest computerised tomography (CT) scanning. However, his serum IgA remains very high and that of IgM is declining, suggestive of ongoing immune dysregulation


The classification of ectodermal dysplasias has been recently reviewed, and over 150 distinct phenotypes identified based on presentation of abnormal teeth, skin, nails, sweat glands, and hair.
4 After our first report, more than 20 patients have been described with features of immunodeficiency associated with X linked anhidrotic ectodermal dysplasia not caused by mutations in ED1 gene causing the common X linked form. These unrelated patients, including ours, were shown to have mutations in NEMO, the gene coding for a molecule with important functions in the NF-B signalling pathway.2,5

The EDA-ID syndrome is clinically heterogeneous; the main features are somewhat milder than those of "classical" anhidrotic ectodermal dysplasia (hypo- or anodontia with conical shaped maxillary incisors, dry skin with hypo- or anhidrosis and hypo- or atrichosis). However, some children manifest a more severe phenotype with osteopetrosis and lymphoedema (OL-EDA-ID; OMIM 300301).6 The immunodeficiency, of which the impaired antibody response to polysaccharide antigens is the most consistent laboratory feature, is severe with significant morbidity and mortality. From early childhood, affected boys suffer from unusually severe, life threatening, and recurrent bacterial infections of lower respiratory tract, skin and soft tissues, bones, and gastrointestinal tract, meningitis, and septicaemia, leading to bronchiectasis, chronic lung disease, intractable diarrhoea, and failure to thrive. The commonly implicated pathogens are Streptococcus pneumoniae, Staphylococcus aureus, Pseudomonas species, Haemophilus influenzae, and mycobacteria. A number of reported children have died with disseminated mycobacterial infections. Replacement IVIg, antibiotic treatment and prophylaxis, and avoiding live vaccines, especially BCG, are the current management guidelines; bone marrow transplantation has been attempted in one patient.6

EDA-ID is inherited as an X linked recessive trait; the female relatives of affected boys may have variable clinical features such as dry and/or hyperpigmented skin, hypodontia, conical teeth, and sometimes increased serum IgA. Indeed, our patient’s mother has conical teeth. Interestingly, a female patient with features of EDA-ID and a heterozygous hypomorphic NEMO mutation has recently been reported.

Functional NEMO is essential for activation of the transcription factor NF-B, which is involved in inducing immune and inflammatory responses; it is important for normal T and B cell development, as well as osteoclast function, skin epidermal cell growth, and maintenance of the vessel architecture. Its targets include genes that produce antiapoptotic factors, cell adhesion molecules, cytokines, and chemokines.5 The "loss of function" NEMO mutation causes incontinentia pigmenti (IP), where the consecutive lack of NF-B activation results in extreme susceptibility to apoptosis, leading to embryonic death in males, and explains the extremely skewed X inactivation seen in females. Finding of hypomorphic NEMO mutations in patients with allelic syndromes of EDA-ID and OL-EDA-ID suggests that the milder phenotype in affected males and both random and skewed X inactivation seen in female carriers are the result of only partial loss of NEMO function.2,5

Both the phenotype-genotype correlation of patients with EDA-ID and the importance of hypomorphic NEMO mutations in disturbed pathways of primarily innate and possibly acquired immunity are currently being investigated.


We are grateful to Professor J-L Casanova for collaboration, support, and encouragement.


Abinun M, Spickett G, Appleton AL, et al. Anhidrotic ectodermal dysplasia associated with specific antibody deficiency. Eur J Pediatr 1996;155:146–7. [CrossRef][Medline]
Doffinger R, Smahi A, Bessia C, et al. X-linked anhydrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-B signalling. Nat Genet 2001;27:277–85. [CrossRef][Medline]
IUIS Scientific Group. Primary immunodeficiency diseases. Clin Exp Immunol 1999;118(suppl 1):1–28. [CrossRef]
Priolo M, Lagana C. Ectodermal dysplasias: a new clinical-genetic classification. J Med Genet 2001;38:579–85. [Abstract/Free Full Text]
Aradhya S, Nelson DL. NF-B signalling and human disease. Curr Opin Genet Develop 2001;11:300–6. [CrossRef][Medline]
Dupuis-Girod S, Corradini N, Hadj-Rabia S, et al. Osteopetrosis, lymphedema, anhidrotic ectodermal dysplasia, and immunodeficiency in a boy and incontinentia pigmenti in his mother. Pediatrics 2002;109:e97. [Abstract/Free Full Text]
Kosaki K, Shimasaki N, Fukushima H, et al. Female patient showing hypohidrotic ectodermal dysplasia and immnodeficiency (HED-ID). Am J Hum Genet 2001;69:664–5. [CrossRef][Medline]

British Medical Journals


A hypermorphic IκBα mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficie



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